Cisplatin (cis-diaminedichloroplatinum(II), cis-DPP) is one of the most widely used drugs for the treatment of solid tumors and hematological malignancies (see Fuertes et al. (2002) Curr. Med. Chem.—Anti-Cancer Agents 2(4):539-551). However, there are several disadvantages associated with the administration of cisplatin, including adverse side effects (neurotoxity, nephrotoxicity, ototoxicity, and emetogenesis) and resistance (intrinsic and acquired). These disadvantages have motivated the search for new platinum anti-cancer agents with the following properties: (1) a broader spectrum of activity than cisplatin, particularly activity against cisplatin-resistant cancers; (2) an improved therapeutic index, either through greater efficacy or reduced toxicity; and/or (3) modified pharmacological properties to improve drug delivery.
Several new platinum anti-cancer compounds have been identified and are currently used in cancer chemotherapy, such as carboplatin (cis-diamine[1,1-cyclobutanedicarboxylate(2-)-O,O′-platinum(II)) and oxaliplatin (cis-L-diaminocyclohexane oxalotoplatinum(II)). Carboplatin is less toxic than cisplatin, but also has less anti-cancer activity and is affected by the same resistance mechanism. Oxaliplatin circumvents cisplatin resistance, but its side effects include dose-limiting neurotoxicity.
Various polynuclear platinum complexes with anti-cancer activity have also been described and are currently in clinical trials, such as the BBR3464 (see U.S. Pat. No. 6,011,166; Manzotti et al. (2000) Cancer Res. 6:2626). However fewer than 1% of the platinum complexes tested for pre-clinical anti-cancer activity-have entered clinical trials in the past 30 years (Fuertes et al. (2002) Curr. Med. Chem.—Anti-Cancer Agents 2(4):539-551).
Several studies in literature and clinical trials have indicated that administration of cisplatin results in oxidative stress and the production of reactive oxygen species such as free radicals. Oxidative stress reduces the rate of cell proliferation and is thought to interfere with the anti-cancer activity of cisplatin, which depends on the rapid proliferation of cancer cells for optimal activity. There is also evidence that the adverse side effects of cisplatin are caused by reactive oxygen species (see, e.g., Leonetti et al. (2003) Int. J. Cancer 104(2):243-50; Pace et al. (2003) J. Clin. Oncol. 21(5):927-31). Thus, there is a need for platinum anti-cancer compounds that elicit a reduced amount of oxidative stress.